Article
Oncology
Anamarija Pfeiffer, Giulia Franciosa, Marie Locard-Paulet, Ilaria Piga, Kristian Reckzeh, Vidyasiri Vemulapalli, Stephen C. Blacklow, Kim Theilgaard-Monch, Lars J. Jensen, Jesper V. Olsen
Summary: The protein tyrosine phosphatase SHP2 plays a crucial role in the oncogenic transformation of AML cells. By stabilizing SHP2 in its autoinhibited conformation, allosteric inhibitors show promise in inhibiting the RAS-ERK pathway and preventing cell proliferation and survival. Combination therapies that target SHP2 and other key enzymes can prevent the development of resistance.
Article
Allergy
Neelam Panchal, Benjamin Christopher Houghton, Elina Vassalou, Adrian J. Thrasher, Claire Booth
Summary: This study demonstrates that the use of SHP2 inhibitors can restore T-cell function in XLP patients and mouse models lacking SAP. The inhibitors improve immunoglobulin and cytokine secretion, offering a potential novel treatment approach for XLP patients.
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
(2022)
Article
Cell Biology
Bogdan Popescu, Carlos Stahlhut, Theodore C. Tarver, Sydney Wishner, Bianca J. Lee, Cheryl A. C. Peretz, Cuyler Luck, Paul Phojanakong, Juan Antonio Camara Serrano, Henry Hongo, Jose M. Rivera, Simayijiang Xirenayi, John A. Chukinas, Veronica Steri, Sarah K. Tasian, Elliot Stieglitz, Catherine C. Smith
Summary: This study reports the preclinical efficacy of co-targeting the key node in MAPK signaling, SHP2, and BCL2 in RTK-driven AML. The allosteric SHP2 inhibitor RMC-4550 suppresses the proliferation of AML cell lines and increases apoptotic dependency on BCL2. RMC-4550 and venetoclax show synergistic lethality in AML cell lines.
CELL REPORTS MEDICINE
(2023)
Article
Immunology
Wei Wei, Mitchell J. J. Geer, Xinyi Guo, Igor Dolgalev, Neville E. E. Sanjana, Benjamin G. G. Neel
Summary: SHP2 acts as an upstream regulator of RAS activation. Through CRISPR/Cas9 screening, LZTR1, MAP4K5, SPRED2/STK40, and INPPL1 were identified as novel genes associated with SHP2 resistance. Understanding the mechanisms of SHP2 resistance and identifying potential combination therapies is important for overcoming drug resistance in cancer treatment.
JOURNAL OF EXPERIMENTAL MEDICINE
(2023)
Article
Medicine, Research & Experimental
Yuyu Zhu, Zhigui Wu, Wei Yan, Fenli Shao, Bowen Ke, Xian Jiang, Jian Gao, Wenjie Guo, Yuping Lai, Hongyue Ma, Dijun Chen, Qiang Xu, Yang Sun
Summary: The study identified SHP2 as a novel regulator of psoriasis, showing that SHP2 inhibition can reduce skin inflammation and may be a promising therapeutic approach for psoriatic patients.
EMBO MOLECULAR MEDICINE
(2022)
Article
Multidisciplinary Sciences
Teklab Gebregiworgis, Yoshihito Kano, Jonathan St-Germain, Nikolina Radulovich, Molly L. Udaskin, Ahmet Mentes, Richard Huang, Betty P. K. Poon, Wenguang He, Ivette Valencia-Sama, Claire M. Robinson, Melissa Huestis, Jinmin Miao, Jen Jen Yeh, Zhong-Yin Zhang, Meredith S. Irwin, Jeffrey E. Lee, Ming-Sound Tsao, Brian Raught, Christopher B. Marshall, Michael Ohh, Mitsuhiko Ikura
Summary: This study demonstrates that KRAS Q61H mutation is not regulated by SHP2, leading to insensitivity to SHP2 inhibitors in pancreatic cancer cells. Furthermore, cancer cells with different KRAS mutations exhibit variable sensitivity to SHP2 inhibitors, potentially due to differences in regulation by GAP and GEF activities, as well as binding affinity to RAF.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Ma Yangchun, Yang Wenyu, Zhou Liang, Li Lipeng, Wu Jingwei, Li Weiya, Du Shan, Ma Ying, Wang Runling
Summary: Studies have shown that the dual allosteric targeted inhibition mechanism of SHP2 involves the combination of SHP099 and SHP844 to inhibit the pharmacological pathway in cells and prevent the substrate from entering the catalytic site.
MOLECULAR DIVERSITY
(2022)
Review
Chemistry, Medicinal
Yihui Song, Xinyu Yang, Shu Wang, Min Zhao, Bin Yu
Summary: This review provides an overview of the structural landscape of SHP2 under physiological and pathological conditions and comprehensively analyzes the binding models of SHP2/inhibitor complexes. The structural features of SHP2 under pathological conditions and co-crystal structures of SHP2/inhibitor complexes will facilitate the design of structure-guided SHP2 inhibitors. Additionally, proteolysis targeting chimeric (PROTAC) based SHP2 degraders show therapeutic promise for cancer therapy.
MEDICINAL RESEARCH REVIEWS
(2022)
Article
Biochemistry & Molecular Biology
Fern Sha, Kohei Kurosawa, Eliezra Glasser, Gayatri Ketavarapu, Samara Albazzaz, Akiko Koide, Shohei Koide
Summary: SHP2 is an important phosphatase/adaptor protein involved in various signaling pathways. In this study, a monobody was developed to selectively inhibit the SHP2 PTP domain, demonstrating high selectivity and binding to conserved residues. The monobody also provided a simple assay for studying the allosteric regulation of SHP2. These findings offer insights into the function and regulation of SHP2 and have implications for drug discovery.
JOURNAL OF MOLECULAR BIOLOGY
(2023)
Review
Chemistry, Medicinal
Ning Wang, Shilin Zhu, Dan Lv, Yajun Wang, Muhammad B. Khawar, Haibo Sun
Summary: Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) is a crucial regulator in the cell cycle and its activating mutations are significant in various cancer developments, making it an essential target for antitumor drugs. However, due to the highly conserved amino acid sequence and positively charged active site of SHP2, finding inhibitors with high affinity and sufficient cell permeability is challenging, thus rendering SHP2 an undruggable target. Nevertheless, the discovery of allosteric regulation mechanisms presents new prospects for transforming undruggable targets into druggable targets. This review highlights the oncogenic mechanism of SHP2 and summarizes the discovery methods of SHP2 allosteric inhibitors, providing novel strategies for designing and improving SHP2 allosteric inhibitors.
DRUG DEVELOPMENT RESEARCH
(2023)
Article
Oncology
Alexander Drilon, Manish R. Sharma, Melissa L. Johnson, Timothy A. Yap, Shirish Gadgeel, Dale Nepert, Gang Feng, Micaela B. Reddy, Allison S. Harney, Mohamed Elsayed, Adam W. Cook, Christina E. Wong, Ronald J. Hinklin, Yutong Jiang, Eric N. Brown, Nickolas A. Neitzel, Ellen R. Laird, Wen - Wu, Anurag Singh, Ping Wei, Keith A. Ching, John J. Gaudino, Patrice A. Lee, Dylan P. Hartley, S. Michael Rothenberg
Summary: PF-07284892, an allosteric SHP2 inhibitor, combined with various oncogenic driver inhibitors, overcame bypass-signaling-mediated resistance in clinical settings. This combination therapy showed significant tumor and circulating tumor DNA responses, extending the duration of overall clinical benefit in patients with targeted therapy resistance in lung, colorectal, ovarian, and pancreatic cancer.
Article
Pharmacology & Pharmacy
Jian Gao, Zhigui Wu, Mingxia Zhao, Rui Zhang, Manru Li, Dongdong Sun, Haibo Cheng, Xianjia Qi, Yuxian Shen, Qiang Xu, Hongqi Chen, Dijun Chen, Yang Sun
Summary: This study reveals the role of SHP2 in innate immunosuppression in the tumor microenvironment. Inhibition of SHP2 can effectively arrest the malignant evolution of tumor cells and activate the interferon signaling pathway in infiltrated myeloid cells. The findings also suggest a potential role of macrophagic SHP2 in colon cancer immunotherapy, especially in patients with MSS phenotype.
ACTA PHARMACEUTICA SINICA B
(2022)
Article
Oncology
Hirohisa Kano, Eiki Ichihara, Hiromi Watanabe, Kazuya Nishii, Chihiro Ando, Takamasa Nakasuka, Kiichiro Ninomiya, Yuka Kato, Toshio Kubo, Kammei Rai, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura
Summary: This study found the potential role of SHP2 in residual cells of NSCLC with ALK/ROS1/EGFR alterations, and showed that combining SHP2 inhibitor SHP099 with molecular-targeted therapy can effectively inhibit cancer cell growth.
MOLECULAR CANCER THERAPEUTICS
(2021)
Article
Chemistry, Physical
Anika J. Friedman, Evan T. Liechty, Levi Kramer, Ankur Sarkar, Jerome M. Fox, Michael R. Shirts
Summary: Protein tyrosine phosphatases (PTPs) are potential drug targets for various diseases, but the design of selective therapeutics is complicated. This study investigates the allosteric inhibition of PTP1B by AD, an unusually selective inhibitor. Molecular dynamics simulations suggest that AD stably interacts with the allosterically influential region of PTP1B. The binding requires a disordered alpha 7 helix, contributing to the selectivity of AD. The findings indicate the potential of AD as a scaffold for building allosteric inhibitors of PTP1B.
JOURNAL OF PHYSICAL CHEMISTRY B
(2022)
Article
Biochemistry & Molecular Biology
Paolo Calligari, Valerio Santucci, Lorenzo Stella, Gianfranco Bocchinfuso
Summary: SHP2 is a critical player in signaling pathways, with activation involving rearrangement of domains and binding to proteins containing phosphotyrosines. Studies show the crystallographic conformation is unstable in solution, with multiple interdomain arrangements present, and activation is coupled to changes in the N-SH2 binding site.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2021)
Article
Biochemistry & Molecular Biology
Markus Niklasson, Renee Otten, Alexandra Ahlner, Cecilia Andresen, Judith Schlagnitweit, Katja Petzold, Patrik Lundstrom
JOURNAL OF BIOMOLECULAR NMR
(2017)
Article
Biochemistry & Molecular Biology
Warintra Pitsawong, Chad A. Haynes, Ronald L. Koder, David W. Rodgers, Anne-Frances Miller
Article
Biochemistry & Molecular Biology
Anne-Frances Miller, Jonathan T. Park, Kyle L. Ferguson, Warintra Pitsawong, Andreas S. Bommarius
Article
Multidisciplinary Sciences
Renee Otten, Lin Liu, Lillian R. Kenner, Michael W. Clarkson, David Mavor, Dan S. Tawfik, Dorothee Kern, James S. Fraser
NATURE COMMUNICATIONS
(2018)
Article
Biology
Warintra Pitsawong, Vanessa Buosi, Renee Otten, Roman Agafonov, Adelajda Zorba, Nadja Kern, Steffen Kutter, Gunther Kern, Ricardo A. P. Padua, Xavier Meniche, Dorothee Kern
Article
Chemistry, Physical
John B. Stiller, S. Jordan Kerns, Marc Hoemberger, Young-Jin Cho, Renee Otten, Michael F. Hagan, Dorothee Kern
Article
Biochemistry & Molecular Biology
Warintra Pitsawong, Pirom Chenprakhon, Taweesak Dhammaraj, Dheeradhach Medhanavyn, Jeerus Sucharitakul, Chanakan Tongsook, Willem J. H. van Berkel, Pimchai Chaiyen, Anne-Frances Miller
JOURNAL OF BIOLOGICAL CHEMISTRY
(2020)
Article
Multidisciplinary Sciences
Adelajda Hadzipasic, Christopher Wilson, Vy Nguyen, Nadja Kern, Chansik Kim, Warintra Pitsawong, Janice Villali, Yuejiao Zheng, Dorothee Kern
Article
Multidisciplinary Sciences
Marc Hoemberger, Warintra Pitsawong, Dorothee Kern
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2020)
Article
Multidisciplinary Sciences
Renee Otten, Ricardo A. P. Padua, H. Adrian Bunzel, Vy Nguyen, Warintra Pitsawong, MacKenzie Patterson, Shuo Sui, Sarah L. Perry, Aina E. Cohen, Donald Hilvert, Dorothee Kern